Autism is a complex developmental disorder that causes problems with social interaction and communication. Symptoms usually start before age three and can cause delays or problems in many different skills that develop from infancy to adulthood. Autism is considered as part of the autism spectrum disorders (ASDs), a group of disorders with similar features. ASDs are diagnosed based on impairment in verbal and nonverbal communication skills and social interactions, and restricted, repetitive and stereotyped patterns of behavior, which can range in impact from mild to significantly disabling. In addition to the classical idiopathic autism, Asperberg's syndrome, Rett syndrome (RTT) and several other genetic disorders including Down's syndrome, Fragile X mental retardation are frequently associated with autism. Although ASD is a multi-factorial disease, it is postulated that an imbalance of excitatory and inhibitory synaptic transmission (E/I imbalance) may underlie the core pathophysiology of the disorder. Mutations of genes such as neurexin 1 (NRXN1), neuroligin3 and 4 (NLGN3/4), SHANK3, PTEN have been associated with autism. In addition, altered regulation of brain derived neurotrophic factor (BDNF) has also been found in autistic patients. In RTT mouse models (i.e., MeCP2 null (- /y) mouse), BDNF expression is shown to be substantially reduced, and elevation of BDNF expression by about two fold via transgenesis, attenuates the MeCP2 knockout mice phenotype. In this application, we hypothesize that activation of BDNF signaling may benefit not only RTT but also other ASDs. Furthermore, in our human embryonic stem cell (ESC)-derived MeCP2 deficient human neuronal model, we observed dramatically enhanced GABAergic neurotransmission, an indication of E/I imbalance due to MeCP2 deficiency, suggesting that our human RTT model might have broad implications in other ASDs. The application of BDNF recombinant protein in therapeutic intervention has not been successful, because BDNF binds to extracellular cholesterol with high affinity which prevents its distribution to different tissues. Moreover, number of TrkB agonist molecules does not cross blood-brain-barrier. Recently, work by our collaborator, Dr. Keqiang Ye's group at Emory University, uncovered a number of small molecule compounds that can effectively activate TrkB activation in the mouse brain and elicit a series of neuroprotective effects when applied peripherally via intra-peritoneal injection or oral ingestion. We showed that these compounds, similar to BDNF, are neuroprotective even for cultured human neurons in serum-starvation or oxidative stress conditions. In this application, we propose to carry out preclinical studies to determine whether the small molecule TrkB agonist(s) can be used for the treatment of ASDs. We will utilize both MeCP2 null (-/y) mice and MeCP2 deficient neurons to perform a comprehensive analysis comprising of behavioral, electrophysiological and gene expression analyses to determine the effects of TrkB agonists in ASDs. Through this study, we hope to evaluate whether our TrkB agonist(s) could be potentially used as a therapeutic intervention for ASDs. PUBLIC HEALTH RELEVANCE: Autism is a complex developmental disorder that causes problems with social interaction and communication, and it is considered as part of the autism spectrum disorders (ASDs), a group of disorders with similar features. In one of the ASDs, Rett syndrome (RTT), BDNF expression is shown to be substantially reduced in mouse models (i.e., MeCP2 null (-/y) mouse), and elevation of BDNF expression by about two fold via transgenesis attenuates the MeCP2 knockout mice phenotype. In this application, we hypothesize that activation of BDNF signaling through small molecule TrkB agonist(s) may benefit not only RTT but also other ASDs.